PARP inhibitors – a breakthrough in breast cancer treatment

In the early 1990s, a geneticist called Mary-Claire King made a phenomenal discovery. A researcher at the University of California, Mary-Claire demonstrated that a single gene on chromosome 17 was responsible for 5 to10 percent of all breast cancer cases. This gene was BRCA1 and its discovery has revolutionised breast cancer treatment and prevention.

A few years later a team led by the influential cancer geneticist, Mike Stratton, and including future Director of the Breakthrough Breast Cancer Research Centre, Alan Ashworth, published the first description of BRCA2 as another breast cancer susceptibility gene.

The weakness

Genetic mutations can be powerful drivers of cancer and it wasn’t surprising to learn that the BRCA genes code for proteins that are intertwined with protecting DNA. In short, the proteins they produce stick to breakages that occur across both strands of DNA, stabilise it and allow other molecules to come in and repair the break. Mutations to BRCA1 or 2 impair this process and as a result, mutations to DNA are not corrected, leaving potentially cancer-causing mutations to ‘infect’ the next generation of cells.

Nature hasn’t been entirely unfair though. The same mutation to BRCA that can cause breast cancer could also be used to defeat it. DNA gets damaged all the time due to the cells’ own processes and external factors such as UV rays or chemical agents. Cells that can’t use BRCA to repair damaged DNA rely heavily on another protein, called PARP, to do the work.

From concept to reality

The potential to attack this PARP system to kill breast cancer cells was first explained in 2005 by Breakthrough scientists Alan Ashworth and Andrew Tutt. They proposed a method called ‘synthetic lethality’, which predicted that by knocking out PARP it would leave a BRCA mutant cell without the ability to repair any damage to DNA, resulting in cell death. Their landmark paper demonstrated for the first time that a new class of drugs called PARP inhibitors was truly effective against cancer cells with BRCA mutations.

Clinical trials were quick to follow and success has been seen in phase 1 and 2 trials for patients with advanced BRCA-associated disease. These trials will tell us just how effective PARP inhibitors are and help us to understand the side effects that may be produced. There is also interest in testing PARP inhibitors in combination with other treatments such as radiotherapy and chemotherapy to enhance their effects.

Back to the lab

Research continues with PARP inhibitors as we try to get to grips with how we can best use these new drugs to save the lives of cancer patients. Basic research is where it started, and that’s where it will need to continue in order to improve the design of the drugs so they work more effectively and more accurately. Last month, Alan and his team published some of the first results characterising a newly designed PARP inhibitor, from experiments carried out in the laboratory. This new design was effective at much lower doses then normal meaning that it could be better tolerated by patients should it reach clinical trials.

This just goes to show that sometimes you have to go back to the start in order to refine and develop your ideas. Tamoxifen is well-established for treating hormone sensitive breast cancer, yet due to the problems experienced with drug resistance in some patients, the research has moved back to the lab to understand how resistance can be combatted. This means investment into research has to be long-term, if we are to make use of discoveries such as Mary-Claire King’s, and turn the findings into something tangible for patients.